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Clinical Studies

Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer

British Journal of Cancer volume 125, pages 1356–1364 (2021)Cite this article

Subjects

Abstract

Background

Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance.

Methods

We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples.

Results

Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes.

Conclusions

We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy.

ClinicalTrials.gov

EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

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Fig. 1: Commonest driver mutations before and after treatment.
Fig. 2: Variants gained and lost after neoadjuvant chemotherapy.
Fig. 3: Frequency and VAF of the most frequently mutated oncogenes and tumour suppressor genes before and after neoadjuvant chemotherapy.
Fig. 4: Copy number variants in pre- and post-neoadjuvant chemotherapy samples.
Fig. 5: Pathway analysis.

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Data availability

Clinical data can be accessed through the EORTC data-sharing platform (for details, see www.eortc.org/data-sharing). NGS data can be accessed through the European Genome-Phenome Archive (https://www.ebi.ac.uk/ega/, cram files EGAD00001003334, study accession number EGAS00001001223). The NGS data are only accessible under a Managed Access Agreement (for details, see www.ebi.ac.uk/ega/dacs).

Code availability

Code is available on request to AC or RI.

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Acknowledgements

We thank the patients, doctors and nurses involved in the EORTC 10994/BIG 1-00 study for their generous participation. We thank Ultan MacDermott and the Sanger Sample Management and Sequencing team for processing the specimens for NGS.

Funding

We thank the Fondation pour la lutte contre le cancer et pour des recherches medico-biologiques, the Site de Recherche Intégrée sur le Cancer—Bordeaux Recherche Intégrée Oncologie Grant INCa-DGOS-Inserm 6046, and the Breast Cancer Working Group EBCC12 grant for financial support. The funding sources had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the study data and the final responsibility for the decision to submit for publication. Trial design, conduct, and analysis were done at the EORTC headquarters, the Institut Bergonié and Wellcome Sanger Institute independently from all funding bodies.

Author information

Author notes

  1. These authors contributed equally: Aikaterini Chatzipli, Hervé Bonnefoi.

Authors and Affiliations

  1. Wellcome Sanger Institute, Cambridge, UK

    Aikaterini Chatzipli

  2. Institut Bergonié, INSERM U1218, University of Bordeaux, Bordeaux, France

    Hervé Bonnefoi, Gaetan MacGrogan, Julie Sentis & Richard Iggo

  3. University of Edinburgh, Edinburgh, UK

    David Cameron

  4. EORTC Data Centre, Brussels, Belgium

    Coralie Poncet

  5. Centre Paul Papin Institut de Cancérologie de l’Ouest (ICO), Angers, France

    Sophie Abadie-Lacourtoisie

  6. Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland

    Alexandre Bodmer

  7. Institut Curie-Hôpital René Huguenin, Saint-Cloud, France

    Etienne Brain

  8. Institute of Oncology, Ljubljana, Slovenia

    Tanja Cufer

  9. Centre René Gauducheau Institut de Cancérologie de l’Ouest (ICO), Nantes, France

    Mario Campone

  10. Centre Alexis Vautrin, Nancy, France

    Elisabeth Luporsi

  11. Centre Henri Becquerel, Rouen, France

    Cristian Moldovan

  12. Centre Paul Strauss, Strasbourg, France

    Thierry Petit

  13. Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

    Martine Piccart

  14. Centre Hospitalier de La Roche/Yon, La Roche/Yon, France

    Franck Priou

  15. Medical University of Gdansk, Gdansk, Poland

    Elsbieta Senkus

  16. Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Khalil Zaman

Authors
  1. Aikaterini Chatzipli
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  2. Hervé Bonnefoi
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  4. Julie Sentis
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  5. David Cameron
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  6. Coralie Poncet
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Consortia

EORTC 10994/BIG 1-00 Consortium

  • Sophie Abadie-Lacourtoisie
  • , Hervé Bonnefoi
  • , Alexandre Bodmer
  • , Etienne Brain
  • , David Cameron
  • , Tanja Cufer
  • , Mario Campone
  • , Elisabeth Luporsi
  • , Cristian Moldovan
  • , Thierry Petit
  • , Martine Piccart
  • , Franck Priou
  • , Elsbieta Senkus
  •  & Khalil Zaman

Contributions

HB, RI and DC conceived the study. DC, HB and EORTC clinical investigators provided clinical samples. CP analysed the clinical data. GMG analysed the histology. JS extracted the DNA. AC and RI analysed the NGS data and made the figures. RI, HB and AC wrote the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Richard Iggo.

Ethics declarations

Ethics approval and consent to participate

The EORTC 10994 clinical trial was registered with ClinicalTrials.gov number NCT00017095 and approved by National and/or Local Ethics Committees in all participating centres. Before registration, all patients signed an informed consent for the trial and for mandatory p53 gene assessment on tumour samples. Patients involved in this substudy gave consent for additional biological research on their tumour samples. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

Not applicable.

Competing interests

The authors declare no competing interests.

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Chatzipli, A., Bonnefoi, H., MacGrogan, G. et al. Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer. Br J Cancer 125, 1356–1364 (2021). https://doi.org/10.1038/s41416-021-01526-3

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  • DOI: https://doi.org/10.1038/s41416-021-01526-3

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